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Zn2+, mitochondria and the induction of ischemic neurodegeneration

Zn2,线粒体与缺血性神经变性的诱导

基本信息

批准号：
8599798
负责人：
JOHN H WEISS
金额：
$ 32.47万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8599798
关键词：
Acidosis Acids Acute Address Binding Brain Brain Injuries Buffers Cations Cell Death Cell Membrane Permeability Cells Cerebral Ischemia Cessation of life Chelating Agents Complex Development Discrimination Divalent Cations Event Excision Generations Glucose Glutamates Hippocampus (Brain)Hour Imaging Techniques Individual Injury Intervention Ions Ischemia Ischemic Brain Injury Ischemic Neuronal Injury Knock-out Lead Mediating Membrane Metals Mitochondria Modeling Monitor Morbidity - disease rate Motion Mouse Strains Movement Mus Nerve Degeneration Neuronal Injury Neurons Neurotransmitters Oxidants Oxidative Stress Oxygen Pathway interactions Phase Play Preparation Presynaptic Terminals Process Proteins Reperfusion Therapy Role Route Seizures Simulate Slice Source Staging Stroke Synapses Synaptic Transmission Testing Therapeutic Intervention Time Transgenic Mice Transgenic Organisms Zinc aging population base brain tissue channel blockers chelation cyclophilin D deprivation effective therapy extracellular hippocampal pyramidal neuron human MT3 protein injured insight loss of function metallothionein III mitochondrial dysfunction mortality neuron loss novel strategies public health relevance response uptake

项目摘要

DESCRIPTION (provided by applicant): Ischemic brain injuries are leading causes of morbidity and mortality to the aging population, but current therapy is poor in part because of our limited understanding of pathogenic mechanisms leading to neuronal loss. A critical trigger of the injury process seems to be acute energy loss, leading to membrane depolarization, excessive release of the excitatory neurotransmitter glutamate and neuronal Ca2+ accumulation. A large and persistent Ca2+ rise ("Ca2+ deregulation") seems to be indicative of neuronal death. Recent evidence implicates critical contributions of another divalent cation, Zn2+, which is abundant in the brain and is normally very tightly regulated. However after ischemia or prolonged seizures, free Zn2+ accumulates in neurons, and observations that Zn2+ chelation is protective implicates a role in neuronal death. Culture studies have revealed that exogenously applied Zn2+ can enter neurons and accumulate in mitochondria and powerfully disrupt their function. However, little is known about mechanisms of injury caused by the accumulation of endogenous Zn2+ in native brain tissues. The proposed project thus seeks to address the following hypothesis: Accumulation of Zn2+ in hippocampal pyramidal neurons contributes critically to the initiation of ischemic neuronal injury, in part via deleterious interactions with mitochondria. Preliminary studies indicate that endogenous Zn2+ accumulates in pyramidal neurons in hippocampal slices subjected to oxygen glucose deprivation (OGD), prior to detectable Ca2+ accumulation, and that the Zn2+ appears to enter mitochondria and contribute to the induction of Ca2+ deregulation and cell death. Aim I will apply fluorescent imaging techniques (using both single cell and bulk loaded indicators) to acute hippocampal slices to examine Zn2+ accumulation in CA1 neurons during OGD, examine its interactions with mitochondria and determine its contributions to Ca2+ deregulation and cell death during acute OGD, and the subsequent reperfusion period. This key aim will seek to provide the first rigorous examination of the above hypothesis, and examine a range of interventions that may offer protection while helping to elucidate the sequence of events involved in the triggering and expression stages of injury. Aim II will use a range of approaches to determine the sources and routes of the injurious Zn2+ accumulation. These issues of "where the Zn2+ comes from" are complex, yet crucial to development of optimal interventions. Aim III will use organotypic slice culture models to examine roles of Zn2+ in the triggering of delayed neurodegeneration (up to 3 days after the OGD), in order to examine downstream injury processes and test therapeutic interventions that may offer protection when delivered well after the ischemia. It is hoped that these studies will provide new insights as to the sequence of events involved in the triggering of ischemic neuronal injury which will lead to new and effective neuroprotective strategies.

描述(申请人提供)：缺血性脑损伤是老年人口发病率和死亡率的主要原因，但目前的治疗方法很差，部分原因是我们对导致神经元丢失的致病机制了解有限。损伤过程的一个关键触发因素似乎是急性能量损失，导致膜去极化，兴奋性神经递质谷氨酸过度释放和神经元钙离子积聚。大而持久的钙离子升高(“钙离子释放”)似乎预示着神经元的死亡。最近的证据表明，另一种二价阳离子锌离子起到了关键作用，锌离子在大脑中含量丰富，通常受到非常严格的调控。然而，在缺血或长时间癫痫发作后，游离的锌离子在神经元中积累，观察到锌离子的螯合具有保护作用，这意味着在神经元死亡中发挥了作用。培养研究表明，外源锌离子可以进入神经元并在线粒体中积聚，从而极大地破坏神经元的功能。然而，内源性锌离子在脑组织中蓄积所致的损伤机制却鲜为人知。因此，该项目试图解决以下假设：锌离子在海马锥体神经元中的积累在缺血性神经元损伤的启动中起关键作用，部分是通过与线粒体的有害相互作用。初步研究表明，缺氧缺糖(OGD)后，内源性锌离子先在海马片锥体神经元中积累，然后进入线粒体，参与钙离子释放和细胞死亡的诱导。目的应用荧光成像技术(使用单细胞和批量加载指示剂)对急性缺氧性脑损伤(OGD)大鼠海马CA1区神经元进行锌离子蓄积的检测，观察其与线粒体的相互作用，以确定其在急性OGD及随后的再灌注期钙离子释放和细胞死亡中的作用。这一关键目标将寻求提供对上述假说的第一次严格检查，并检查一系列可能提供保护的干预措施，同时帮助阐明在损伤的触发和表达阶段涉及的一系列事件。AIM II将使用一系列方法来确定有害的锌积累的来源和途径。这些“锌离子从哪里来”的问题很复杂，但对制定最佳干预措施至关重要。目的利用器官型脑片培养模型研究锌离子在延迟性神经退行性变(OGD后3天内)的触发作用，以检测下游损伤过程，并测试在缺血良好后给予保护的治疗干预措施。希望这些研究能对缺血性神经元损伤的触发过程提供新的认识，从而找到新的有效的神经保护策略。